Polymorphic compounds, also known as allotrophic compounds, are compounds which can exist in two or more forms which although comprised of the same elemental components exhibit significantly different physical and chemical properties. The difference between the forms involves either a) the crystalline structure b) the number of atoms in the molecule of a gas, or c) the molecular structure of a liquid. Carbon for example, exists in several different polymorphic crystalline forms, diamond, carbon black and graphite.
Terazosin is chemically identified as 2-(4-(2-tetrahydrofuroyl)1-piperazine-l-yl)-4-amino-6, 7-dimethoxy quinazoline. This drug is used in the treatment of hypertension, benign prostatic hyperplasia and congestive heart failure. The drug is represented by the formula: ##STR1##
The method of preparation of 2(4-(2-tetrahydrofuroyl)-1-piperazine-1-yl)-4-amino-6, 7-dimethoxy quinazoline was first described and claimed in U.S. Pat. No. 4,026,894 to Winn et al. The compound synthesized by this method was identified and is referred to as the Form-I non-solvated crystalline polymorph. A pharmaceutically acceptable salt of terazosin is disclosed and claimed in U.S. Pat. No. 4,112,097, also to Winn et al.
The terazosin hydrochloride dihydrate salt and methods of preparation are disclosed in U.S. Pat. No. 4,251,532 to Roteman et al. The dihydrate form is allegedly more stable during storage in bulk form and more stable in solution and therefore more suitable for parenteral administration. U.S. Pat. No. 5,294,615 discloses the anhydrous non-solvated crystalline Form-II polymorph of terazosin hydrochloride, which is physically different from Form-I and allegedly has unexpectedly uniform bioavailability. The published Japanese Patent Application No. 5-78352 describes and claims a process of making a novel terazosin hydrochloride methanolate intermediate and the inter-conversions of the same to six-non-solvated crystalline polymorphs of terazosin hydrochloride.
U.S. Pat. No. 5,212,176 to Kyncl teaches the preparation of an enantiomeric excess of R(+) terazosin and its pharmaceutically acceptable salts. This enantiomer is disclosed as being useful in a variety of pharmaceutical dosage forms.
U.S. Pat. No. 5,412,095 to Morley et al. describes and claims processes for making a non-solvated crystalline terazosin polymorph Form-III and its methanolate intermediate. The methods for the conversion of the methanolate intermediate to the non-solvated crystalline polymorphs of terazosin involve using a variety of polar solvents such as ethanol/acetone for Form-I, ethanol for Form-II and dry acetone, ethanol, methylethylketone (2-butane) for Form-III in different experimental procedures. The methanolate intermediate is distinct from both the Form-I and Form-II intermediates which are easily isolated therefrom. Non-solvated terazosin hydrochloride Forms I, II, III and the dihydrate can be prepared using the methanolate intermediate. These compounds have been studied and distinguished using different instrumentation techniques such as x-ray diffraction, C.sup.13 Nuclear Magnetic Resonance, (NMR) Fourier Transform Infrared spectrometry (FTIR) and Differential Scanning Calorimetry (DSC).
U.S. Pat. No. 5,362,730 to Bauer et al. discloses and claims a process for the preparation of terazosin monohydrochloride in which the dehydrate form or the anhydrous Form 1 terazosin hydrochloride is contacted with a polar organic solvent such as C.sub.1 -C.sub.6 ketones or mixtures thereof. The anhydrous crystalline polymorph of terazosin monohydrochloride so produced is also claimed in a pharmaceutical composition.
The present invention comprises a novel polymorph form of terazosin hydrochloride monohydrate, Form IV and a process for its preparation without the need for the formation and isolation of an intermediate as required by the processes of the prior art.